Psychiatric diseases including affective clinical patterns (schizophrenia, anxiety, depression) form a great challenge to the medical science. About 1% of the population suffers from schizophrenia. However, the recent drug therapy is not completely suitable for the treatment of the disease. Clinically, schizophrenia is characterized by two syndromes which are fundamentally different as to etiology and response to drug therapy. These are the so called positive or productive symptoms (hallucination, delusions) and negative or deficit symptoms (the emotional life becomes empty, dumbness) [Crow, T. J., Brit. Med. J., 280, 66 (1980)]. It is believed that the formation of the productive symptoms is due to the hyperfunction of the mesolimbic dopaminergic system [Kahn, R. S. and Davis, K. L., The Fourth Reneration of Progress, editor: Bloom, F. E. and Kupfer, D. J., Raves Press, New York, p 1215 (1995)], and these symptoms can be well controlled by the so called classic neuroleptics (haloperidol, chlorpromazine). However, in case of the negative symptoms, the hypofunction of the mesolimbic dopaminergic system is characteristic [Knable, M. B. and Winberger, D. M., Psychopharmacology, 11, 123 (1997)], and then the drugs mentioned above are ineffective, moreover, they can cause a deterioration of the negative symptoms. The so called conventional neuroleptics (haloperidol, chlorpromazine) which are primarily dopamine D2 receptor antagonists dominate the therapy up to this time. Consequently, as mentioned above, they have numerous unfavourable side effects and are inefficient in one of the syndromes of schizophrenia (negative symptoms) [Ellenbroek, B. A., Pharmacol. Ther., 57, 1 (1993)].
After the discovery of the 5-HT2A receptors [Leysen et al., Biochem. Pharmacol., 27, 307 (1978)], the role of these receptors was upgraded in the therapeutical effect against schizophrenia. Clozapine was the first drug that bound to the 5-HT2A receptors more strongly than to the D2 receptors and did not have the unfavourable side effects which characterize the conventional drugs, furthermore, clozapine controlled also the negative symptoms well [Meizer, H. Y., Schizophr. Bull., 17, 263 (1991)]. Clozapine was followed by several newer, subsequent generation neuroleptics such as olanzapine, seroquel etc., however, clozapine can be considered the standard atypical neuroleptic. Also the newer atypical drugs mentioned above are equally effective in case of the positive symptoms (hallucination, delusions) and negative ones (emptiness of the emotional life, dumbness) characterizing schizophrenia.
3-(1-substituted-4-piperidinyl)-1,2-benzisoxazole derivatives having neuroleptic activity are described in the article J. Med. Chem., 28(6), 761–769 (1985). 3(2H)-pyridazinone derivatives having antiarrhythmic effect are known from U.S. Pat. No. 5,395,934.
The aim of the invention is to prepare novel compounds having neuroleptic effect which influence both syndromes of schizophrenia favourably, are more effective than clozapine and possess neither extrapyramidal nor endocrinic side effects.